horizons 2013: connecting the aapm and the nci ps-oc ... · shorter time course – targit trial...

Horizons 2013: Connecting the AAPM and the NCI PS-OC Program

Clinical Applications of Physical Sciences in Breast Oncology: One Cancer Surgeon’s

Perspective

E. Shelley Hwang MD, MPH Duke Comprehensive Cancer Center

November 7, 2013

Applications of Physical Sciences in Breast Oncology

• Diagnosis – Breast tomosynthesis – 3D CT – Breast density

• Treatment – Surgery—Margin assessment – Radiation therapy

• Prevention/Surveillance/Prognosis (PSOC) – Breast Density – CTCs – Tumor heterogeneity

Breast Cancer Diagnosis • More than 1 in 8 women in the United States will be diagnosed

with breast cancer; 250,000 diagnosed annually • Almost 40 million mammograms are done every year—

estimated cost of $5 -7 billion • Mammographic screening was implemented in the 1980’s

– Only 25% >5 MMG – Associated with reduction in breast cancer specific

mortality – Guidelines controversial

• New technologies – Tomosynthesis – 3D breast CT

Joseph Lo, Duke University

Breast Tomosynthesis improves mammography sensitivity and specificity

• 2D mammo (L) missed cancer, easily seen on 3D tomo slice (R)

??? IDC

Contrast-enhanced mammo/tomo

Standard FFDM, lesions obscured by anatomy

Standard tomo, remove overlap w/ 3D acquisition

Dual energy FFDM, subtract anatomy by energy cancelation

Temporal subtraction tomo, temporal + 3D to remove anatomy


MMG tomosynthesis

Cross-modality approach to measure breast tomosynthesis density

• Probabilistic model uses both anatomy and voxel values • Train with MRI, apply cross-modality to tomo

MRI: convert original image (left) to ground truth (right), which can train Hidden Markov Model to segment fibroglandular vs adipose tissue, then apply to tomo.

Tomo: original image (left), segmented dense tissue (mid), much better than traditional thresholding (right) that grossly overestimates density


3-D Breast Computerized Tomography (CT)

Lead-lined walls & doors

Radiopaque & contoured patient support

Laser positioning cross-hairs

Fully-3D motion of x-ray & digital detector

NO breast compression

Images acquisition in 10-12 minutes

McKinley et al. Proc. IWDM. Springer-Verlag. (2012):442-449. Zumatek / Duke

3D CT pilot: Reader Results

• Preliminary studies indicate fully-3D breast CT has significant advantage over digital mammography in tumor detection

• Smallest observer detectable size in dense breast:

Detection sensitivity at 50X smaller volume

Digital Mammography

Digital Mammography – 7.8mm

Breast 3D CT Breast CT – 2.1mm

McKinley et al. SPIE Med. Imag. 6150(1D):1-10, 2007. Zumatek / Duke

Photo of Breast Tissue

Cadaver breast measurements have Mean Breast Dose (MBD) <4.5 mGy per breast for fully-3D breast CT

MMG dose: 3.7 mGy

2D Dose ‘Heat’ Scale

mGy MBD = 4.3 mGy

Crotty et al. Medical Physics 38(6):3232, 2011. Zumatek / Duke

3D CT pilot: Dosimetry Assessment

Sagittal Coronal MLO

McKinley et al. Proc. IWDM. Springer-Verlag. (2012):442-449. Zumatek / Duke

3D CT pilot: Image comparison between MMG and 3D CT

Sagittal Coronal Axial

Madhav et al. 2007. IEEE Conference Record NSS/MIC, 5:3781. Duke

Combined dedicated breast SPECT and CT at Duke Systems are combined on the same gantry Illustrates utility of functional SPECT information along

with anatomy from bCT

Functional imaging: 3D CT/PET

Breast Cancer Treatment

Almost 40,000 women undergo at least one repeat surgery

Optical spectral mapping of reflectance spectroscopy leverages optical contrast

between normal and cancer tissue

1 Volynskaya, 2008; Zhu., 2006: Zhu, 2008; Palmer, 2006; Ghosh, 2001; Cerussi, 2006;

Hemoglobin absorption

Cell scattering

β-carotene absorption

Collagen scattering

“Negative margin”

“Positive margin”

Contrast 1 • β-carotene • Hemoglobin • Scattering

Shift to lower values

Rapid Surveillance of a Tumor Margin in < 30 seconds

Bydlon and Brown et al, PLOS one,2013

Pixe

l

Log(Rc) (a.u.)

5 10 15 20

5101520253035

0

1

2

3

4

5Positive

DCIS

A

A+FG

FA

Negative

5 10 15 20 25 30

51015202530M

argin

Size

(mm

)

50

50

530

0 5 10 150

0.5

1

β-carotene/<µs'> (µM-cm)

Cum

ulat

ive P

roba

bility

NegativePositive

A B Shift to lower values

Predictive models for margin assessment (75 patient study)

Image variables

• Median • Quantile thresholds • KS-statistic

Conditional Inference Tree

Variable 1

<3 >3

Negative Variable 2

<5 >5

Negative Positive

Bydlon and Brown, PloS One, 2013

Samples (n) Se (%) Sp (%) PPV NPV

All (88) 74 86 85 75

Low Density (48) 65 92 88 74

High Density (40) 83 76 83 76

Radiation Therapy for breast cancer: Standard Approach

• External beam radiotherapy administered daily on an outpatient basis for 4-6 weeks

• Treatment considerations:

– Skin reactions – Fatigue – Exposure of healthy tissues (lung,

heart) – Access to radiation – Cost

Novel Techniques of Administering Breast Radiation

• Hypofractionation: giving larger radiation doses over shorter time course – TARGIT trial

• Intraoperative radiation • Given for 30 min to lumpectomy site only • Part of an international prospective randomized

trial—endpoints recurrence, cosmesis – Preoperative radiosurgery

Intrabeam single-dose radiation for breast cancer

• A complete system to deliver Intra-op RT directly into tumors, or tumor cavities.

• Generates and delivers a high dose of low energy (50KeV) x-rays in a precise, spherical distribution pattern around a point source

1. Surgeon performs the lumpectomy 2. Surgeon sizes the cavity for the appropriate size applicator

Intrabeam Radiotherapy


3. The Intrabeam is draped;applicator is affixed to the PRS 4. Surgeon places X-ray source and applicator inside cavity and

purse string stitch is used to approximate the tissue to the applicator for even dose distribution

5. Surgeon uses sterile shields to protects delicate tissues

6. Radiation Oncologist sets the prescribed dose (5 gy to 1 cm) into the control console

7. Optional shielding is applied around the applicator to protect against scatter

8. Radiation treatment is delivered in 21 – 30 min.


HR 0.94 Logrank p=0.56

HR 0.47 Logrank p=0.009

Breast Cancer Deaths 36 events

Non-Breast Cancer Deaths 52 events

Vaidya JS, et al: SABCS 2012, Abstract S4-1

IBTR (34 events)

HR 2.05 (1.01-4.25) Logrank p=0.042

Difference 2.01%

(0.32-3.7)

10% 5% 0%

0 1 2 3 4 5 years

PREOPERATIVE PARTIAL BREAST RADIOSURGERY

cT1N0M0 breast cancer

Verify biopsy clip

Planning MRI/CT

Treatment

Dose Escalation Schedule

Dose Level RSU Dose

Level 1 15 Gy

Level 2 18 Gy

Level 3 21 Gy

Research MRI

Lumpectomy/SLN, biopsy

Acute toxicity evaluation

Dose Delivery • Prone position

– Rare supine • No breast immobilization • Kv/CBCT confirmation

Accrual • Opened 1/2010 • 1st patient treated: 8/10 • 2nd: 3/2011 • Completed with 32

patients: 3/2013

Objectives • Determine the maximum dose • Evaluate safety as measured by

acute (3-4 weeks) grade 3, 4 toxicity

• Local control/cosmesis • Paired tissue/imaging correlatives • Provide standard post-operative

RT for high risk features

Horton J et al; ASTRO 2013

• Phase I Outcomes – Median follow-up:

• 6.9 months – 32 patients treated:

• 25 invasive • 7 DCIS

– No acute grade 3, 4 toxicities

– No recurrences to date

PREOPERATIVE PARTIAL BREAST RADIOSURGERY:

Time Point Patient-Reported

Cosmetic Outcome Physician Reported Cosmetic Outcome

Baseline 31 excellent/good 32 excellent/good (n=32) 1 fair/poor

6 months 22 excellent/good 20 excellent/good

(n=22|20)

12 months 10 excellent/good 8 excellent/good (n=11|10) 1 fair/poor *2 fair/poor

24 months 4 excellent/good 4 excellent/good

(n=5) 1 fair/poor *1 fair/poor *fair/poor outcomes both in patients receiving post-operative RT

Horton J et al; ASTRO 2013

PSOC Collaborations

Association Between Breast Density and Breast Cancer Risk

• Breast density strongly correlated with breast cancer risk (RR 4-6) • Heritable component (twin studies): 60% • Responsive to changes in exogenous and endogenous hormones

– HRT – Luteal phase of menstrual cycle – Menopause

• Lifestyle/modifiable

component: – Late age at first birth – Nulliparity – HRT

Provenzano PP, BMC Med 2006

Epithelial cells are intimately connected to surrounding collagen in the ECM

In soft tissues, type I collagen accounts for 80-90% of all extracellular matrix (ECM) proteins general:

maintaining structural integrity contributing tensile strength to tissue

more specialized role in regulation of: cell polarity migration survival

Normal stroma: parallel orientation with respect to epithelium; newly synthesized peritumoral stroma loosely woven morphology and non-planar orientation

high MD associated with altered type I collagen production and altered collagen remodeling

http://www.biomedcentral.com/1741-7015/4/38/figure/F1?highres=y

Increased collagen matrix density directly promotes epithelial cell proliferation. (a) Actin staining to visualize MCF10A human mammary epithelial cells cultured within low (1.3 mg/ml) and high-density (3.0 mg/ml) collagen gels for 21 days (actin, green; nuclei, blue). Left: Two well-differentiated acini structures formed in low-density matrices. Right: A single, less organized colony. (b) Increased proliferation of mammary epithelial cells cultured within high-density matrices, measured by increased detection of the Ki67 antigen, a marker of proliferation.

Provenzano PP, BMC Med 2008

Epithelial cells respond to the stiffness of the collagen matrix

Collagen alignment facilitates invasion

Schedin P , Keely P J Cold Spring Harb Perspect Biol 2011

Clinical/Translational implications for human breast cancer

• Geospatial relationship of breast stiffness – within and between breasts (areas of increased risk?) – with proximity to tumor

• Relationship/proximity to histophenotype & molecular

subtype • Predictor of invasive potential? Metastatic potential?

Treatment response?

Methods to measure the ECM mechanical properties

Alfred Au

20 um sections (3) 5 um sections (5) 5 um sections (5)

H and E H and E

Mechano H&E IHC molecular

PHOTO DETECTOR

LASER

CANTILEVER

Atomic Force Microscope

Stiffness Maps

Normal Fibroadenoma Tumor

(kPa)

Malignant Phenotype

Irene Acerbi

kP

Malignant Phenotype

NORMAL ER+ve TUMOR ER-ve TUMOR

Structured illumination polarized microscopy (SIM-POL) imaging visualizes ECM orientation

Jan Liphardt UCBerkeley Quanming Shi

Malignant phenotype in breast tissue is associated with higher collagen content (orthogonal PS signal), higher Fibronectin deposition, higher linearization of collagen (as seen with Second Harmonics Generation) and higher collagen cross-linkling (LysilOxidase LOX) staining.

This may be changing the mechanical properties of the tissue.

ECM remodeling and malignant phenotype

LOX DAPI 20 μm

Differential Gene Expression in BRCA 1(+) stroma (prophylactic mastectomy)

BRCA1 mutation leads to dominant stromal phenotype? Enrichment analysis of the 1496 genes differentially expressed between BRCA1 group

and normal regardless of cell type

Polyak K, unpublished data

Mechanical signaling pathways

Schedin P , Keely P J Cold Spring Harb Perspect Biol 2011

MRI technique was compared to 2-dimensional mammography and showed a moderate correlation in an unselected group (R2=0.67) but very low correlation in patients with high breast density (R2=0.26), suggesting that there exists a compositional component to breast MR density that does not overlap with MMG breast density

Klifa C et al, MRI 2010

Constituents of mamographic density and breast MRI differ

Swaby R et al, BMC Medicine, 2011

CellSearch technology • relies on immunomagnetic bead

enrichment step of EpCAM(+) cells

• Enrichment step can result in intact cells or fragmented cells

• 49% of Stage IV breast cancer CTC(+) (Cristofanilli, 2004)

CTC (CellSearch) prognostic in metastatic breast cancer

CTC are prognostic in early stage invasive breast cancer

11/8/2013 42 Molloy TJ, Br Ca Res 2011

PSOC0039 –0044: HD-CTC vs. CellSearch

43

Cancer Type HD-CTCs/mL HD-CTCs/7.5 mL CellSearch/7.5 mL Breast #1 49.3 369 1 Breast #2 87 652 0 Breast #3 33.4 250 1 Breast #4 199.3 1494 1 Breast #5 5 37 23

Prostate #1 2.3 17 0 Prostate #2 8.4 63 3 Prostate #3 107.3 804 21 Prostate #4 1.3 9 0 Prostate #5 150.5 1128 1 Prostate #6 0 0 0 Prostate #7 1.4 10 4 Prostate #8 1.5 11 1 Prostate #9 145.3 1089 6

Prostate #10 57.6 432 0

Process for Finding HD-CTC

Prepare Cartridges Scan Cartridges

CTC Reports/ Professional Analysis

Technical Analysis 2

4

3

5

6

Run Algorithms

Store Cartridges

Thaw and process cartridges

7

CTC ID Centrifugation & Plating

CTC Assay

1

555 nm Morphometry

647nm

All 103 CTCs identified on 1 slide from Stage IV prostate cancer patient (Kuhn: 1129/7.5mL; CellSearch: 1/7.5mL)

High Definition CTC = HD CTC

An Event that has an intact nucleus (DAPI+) And has cytokeratin (tissue origin marker) And has NOT CD45 (leucocyte origin

marker) And is morphologic distinct from

surrounding leucocytes And is displayed in diagnostic pathology

quality

11/8/2013 46

Benign Patients

72.3

17.9 12.0

1.8 0.8 0.0 0.0

10.0

20.0

30.0

40.0

50.0

60.0

DeB1920DeB1931DeB1930DeB1923DeB1907DeB1903

cells

/mL

CTC/mL

2.8 2.5 1.7 0.9 0.6 0.0 0.0

10.0

20.0

30.0

40.0

50.0

60.0


cells

/mL

“Apoptotic”/mL

13.2 9.1 9.0

3.6 2.8 2.8 0.0

10.0

20.0

30.0

40.0

50.0

60.0


cells

/mL

Low CK/mL

11.9 6.3 6.2 5.8 3.2 2.8

0.0

10.0

20.0

30.0

40.0

50.0

60.0


cells

/mL

Small CK/mL

11/8/2013 47

Malignant Patients

47.2

35.8 27.9

15.4 11.5

5.9 5.3 3.5 3.2 0.4 0.0

10.0

20.0

30.0

40.0

50.0

60.0

cells

/mL

Small CK/mL

36.5 27.5

17.1 16.7 12.4 10.6 10.4

3.9 2.8 0.4 0.0

10.0

20.0

30.0

40.0

50.0

60.0

cells

/mL

Low CK/mL

5.6 4.1 2.0 2.0 1.3 0.9 0.8 0.7 0.4 0.0 0.0

10.0

20.0

30.0

40.0

50.0

60.0

cells

/mL

“Apoptotic”/mL

270.6 176.9

4.6 0.4 0.0 0.0 0.0 0.0 0.0 0.0 0.0

10.0

20.0

30.0

40.0

50.0

60.0

cells

/mL

CTC/mL

CTC CK Intensity

CK

Inte

nsity

DeB19

07

DeB19

20

DeB19

23

DeB19

30

DeB19

31

DeB19

14

DeBTN12

0005

0

DeBTN12

0005

1

DebTN12

0005

2

0

20

40

60

80

100

11/8/2013 48

Cytokeratin and EpCAM Intensity for all CTCs

Very dim CK

Benign

Malignant

CTC EpCAM Intensity

EpC

AM In

tens

ityDeB

1907

DeB19

20

DeB19

23

DeB19

30

DeB19

31

DeB19

14

DeBTN12

0005

0

DeBTN12

0005

1

DebTN12

0005

2

0

20

40

60

80

100

Benign

Malignant

CTCs and Diagnosis

11/8/2013 49

Benign vs Malignant

Patient DiagnosisC

TC/m

L

Benign

Malignan

t0

100

200

300

Benign vs Malignant

Patient Diagnosis

Apop

/mL

Benign

Malignan

t0

2

4

6

8

10

Benign vs Malignant

Patient Diagnosis

Low

CK

/mL

Benign

Malignan

t0

10

20

30

40

Benign vs Malignant

Patient Diagnosis

Smal

l CK

/mL

Benign

Malignan

t0

10

20

30

40

50

CTC Benign Malignant Mean 17.47 45.25

Std. Deviation 27.8 96.65 Std. Error 11.35 30.56

Apoptotic Benign Malignant Mean 1.417 1.78


Low CK Benign Malignant Mean 6.75 13.83


Small CK Benign Malignant Mean 6.033 15.61


50

DeB1920

DeB1930

DeB1931

3 Benign Patients

51

DeBTN1200050 2 Malignant Patients

DeBTN1200052

Within-tumor diversity as a predictor of cancer development risk. Tumors with low diversity (left) contain few clones and so are unlikely to contain a clone with malignant potential, that is able to adapt to the changing environment within an evolving tumor.

Within-tumor diversity and risk of cancer progression

Circos plots of two samples (blue and green) from the same lung adenocarcinoma. This is an example of a patient with high levels of LOH and divergence between the two regions. Other patients had high levels of LOH but low divergence scores. B. Kaplan-Meier survival curves for all 58 lung adenocarcinoma patients included in the study, stratified by genetic divergence as measured on SNP arrays.

Heterogeneity is associated with clinical outcome

DCIS is Part of a Continuum of Pathologic Change

Burstein HJ, et al. N Engl J Med. 2004.

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Summary

• The physical sciences are the cornerstone of cancer diagnosis and treatment

• Advances in engineering >>> more effective therapy with less toxicity

• “wild side” of physical sciences will be the source of future advances in oncology

Collaborators • Bay Area PSOC

(Liphardt/Weaver) • Scripps PSOC (Kuhn) • Maley Lab (UCSF) • UCSF Breast Oncology

Program

• Funding: – PSOC/SAIC-F – Komen – Breast Cancer Research

Foundation/TBCRC

• Duke: – Jeff Marks Lab – Joseph Lo Lab – Martin Tornai Lab – Nimmi Ramanujam Lab – Janet Horton and Duke

Radiation Oncology Department

– Duke Cancer Institute

• Patients and their families who participate in research

horizons 2013: connecting the aapm and the nci ps-oc ... · shorter time course – targit trial...

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